Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors.

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

Novel acridinedione derivatives: design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies.

A new scaffold N-(9-(ortho/meta/para-(benzyloxy)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl) isonicotinamide (H1-3) was discovered as a hSIRT1 inhibitor through virtual screening of in-house database. Based on these hits, a library of compounds were designed, synthesized and tested for in vitro hSIRT1 activity. The most potent compound 4d in the series showed a significant inhibition of SIRT1 activity. Further antitumor studies of compound 4d, showed a dose dependent increase in acetylation of p53K382 and decrease in SIRT1 with an IC(50) of 0.25 µM in MDA-MB231 breast cancer cell lines. Individual 3D-QSAR analysis using Schrödinger showed distribution of hydrophobic and non polar positive co-efficient at ortho position essential for bioactivity based on 4d.

Synthesis of highly potent novel anti-tubercular isoniazid analogues with preliminary pharmacokinetic evaluation.

Thirty two novel isoniazid analogues were prepared by one-pot three component condensations of isoniazid (INH), 3-mercaptopropionic acid and various aryl/heteroaryl aldehydes. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and cytotoxicity. Among the compounds, compound N-(2-(4-(benzyloxy) phenyl)-4-oxo-1,3-thiazinan-3-yl) isonicotinamide (17) inhibited MTB with MIC of 0.12 µM and was three times more potent than INH. The main pharmacokinetic parameters after intravenous administration (10 mg/kg body weight) in male Wistar rats viz. t(½), K(el), mean plasma clearance and mean volume of distribution were found to be 1.14±0.20 h, 0.62±0.10 h(-1), 22.48±0.16 mL/kg/min and 1.99±0.49 L, respectively. The systemic absorption was slow after oral administration (50 mg/kg body weight). The peak plasma concentration was found to be 1.31±0.06 µg/mL attained in 3 h. The bioavailability was found to be 16.7%.

Microwave assisted one-pot synthesis of highly potent novel isoniazid analogues.

A series of novel isoniazid (INH) analogues were synthesized by microwave assisted one pot reaction of INH, various benzaldehydes and dimedone in water with catalytic amount of DBSA. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant Mycobacterium tuberculosis (MDR-TB). Among the 29 compounds, compound N-[9-[2-(benzyloxy)phenyl]-3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-10(1H)-acridinyl]isonicotinamide (12) inhibited MTB with MIC of <0.17 µM and MDR-TB with MIC of 0.69 µM.

Synthesis and antimycobacterial evaluation of novel Phthalazin-4-ylacetamides against log- and starved phase cultures.

Twenty four novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid amides were synthesized from phthalic anhydride and were subjected to in vitro and in vivo evaluation against log- and starved phase of mycobacterial species and Mycobacterium tuberculosis isocitrate lyase enzyme inhibition studies. Among the compounds screened, 2-(2-(4-bromo-2-fluorobenzyl)-1,2-dihydro-1-oxophthalazin-4-yl)-N-(2,6-dimethylphenyl)acetamide (5j) inhibited all eight mycobacterial species with MIC's ranging from 0.08 to 5.05 microm and was non-toxic to Vero cells till 126.43 microm. Four compounds were tested against starved culture of Mycobacterium tuberculosis and they inhibited with MIC's ranging from 3.78 to 23.2 microm. Some compounds showed 40-66% inhibition against Mycobacterium tuberculosis isocitrate lyase enzyme at 10 microm. The docking studies also confirmed the binding potential of the compounds at the isocitrate lyase active site. In the in vivo animal model, 5j reduced the mycobacterial load in lung and spleen tissues with 1.38 and 2.9-log10 protections, respectively, at 25 mg/kg body weight dose.

A microwave-assisted, facile, regioselective Friedländer synthesis and antitubercular evaluation of 2,9-diaryl-2,3-dihydrothieno-[3,2-b]quinolines.

A series of 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines have been synthesized regioselectively by Friedländer annulation of 5-aryldihydro-3(2H)-thiophenones and 2-aminobenzophenones in the presence of trifluoroacetic acid in good yields under microwave irradiation at 100 degrees C. The 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the 17 compounds screened, 7-chloro-2-(2,4-dichlorophenyl)-9-phenyl-2,3-dihydrothieno-[3,2-b]quinoline and 7-chloro-2-(3-nitrophenyl)-9-phenyl-2,3-dihydrothieno[3,2-b]quinoline display maximum activity with MIC of 0.90 and 0.95 muM against MTB and MDR-TB respectively.

5-Nitrofuran-2-yl derivatives: synthesis and inhibitory activities against growing and dormant mycobacterium species.

Eighteen 5-nitrofuran-2-yl derivatives were prepared by reacting 5-nitro-2-furfural with various (sub)phenyl/pyridyl thiosemicarbazide using microwave irradiation. The compounds were tested for their in vitro activity against tubercular and various non-tubercular mycobacterium species in log-phase and 6-week-starved cultures. Compound N-(3,5-dibromopyridin-2-yl)-2-((5-nitrofuran-2-yl)methylene)hydrazinecarbothioamide (4r) was found to be the most potent compound (MIC: 0.22 microM) and was 3 times more active than standard isoniazid (INH) and equally active as rifampicin (RIF) in log-phase culture of Mycobacterium tuberculosis H37Rv. In starved M. tuberculosis H37Rv, 4r inhibited with MIC of 13.9 microM and was found to be 50 times more active than INH and slightly more active than RIF.